Mock pharmacology Flashcards
describe the key aspects of absorption and distribution
Prednisolone is a synthetic glucocorticoid used for its anti-inflammatory and immunosuppressive effects. Prednisolone is almost completely and rapidly absorbed in the small intestine especially in the duodenum after oral administration, with about 70% bioavailability. prednisolone’s lipophilic and small molecular properties allows it to be absorbed via passive diffuse across the phopholipid bilayer. Also driven by the concentration gradient from the GI lumen (where the drug concentration is high) to the bloodstream (where the concentration is lower). This process does not require ATP or specific transporters.
Peak plasma concentration occurs within 1-3 hours.
The half-life of prednisolone is 2-3 hours
Prednisolone is 65-91% protein-bound, it binds tightly to corticosteroid-binding globulin (CBG): transcortin, with the remaining drug either bound to albumin or remaining unbound. CBG acts as both a transporter and a reservoir, shuttling the drug through the bloodstream to various tissues and slowly releasing it over time. While bound to CBG or albumin, prednisolone is inactive because it is too large to cross cell membranes and cannot bind to glucocorticoid receptors. The free (unbound) form of prednisolone is pharmacologically active and can cross cell membranes to bind to glucocorticoid receptors in target cells.
Prednisolone can cross the blood brain barrier through simple diffusion and can basically reach all brain cells and binds to GR to exert its effect. 88% of prednisolone is inactivated as it crosses the placenta and small amounts pass into breast milk. Extra monitoring of mother and foetus growth may be required.
describe the key aspects of metabolism and elimination
Prednisone under goes first-pass metabolism in the liver, to become its pro-drug prednisolone. The first pass effect does not significantly affect prednisolone’s bioavailability (70%). The half-life of prednisolone is 2-3 hours and is longer in people with liver disease due to lower albumin levels.
For phase 1 metabolism prednisolone is mainly metabolised in the liver, which it enters via the hepatic portal vein. Liver cells called hepatocytes which contain CYP3A4 enzymes needed to metabolise prednisolone. Prednisolone undergoes phase 1 metabolism which involves oxidation, reduction or hydrolysis reactions. Here the drug is to convert to more polar and water-soluable molecules.
It is important to remeber that drugs such as carbamazepine and phenytoin (inducers) will increase the metabolic rate of prednisolone resulting in a sub-therapeutic effects. P450 enzyme inhibitor drugs such as, Ketoconazole and fluconazole will slow down the rate of prednisolone metabolism causing toxicity.
Prednisolone undergoes Phase II metabolism, to excrete any molecules which are still lipid soluable by conjugation with sulfate and glucuronic acid, this makes make the molecules more water-soluble and polar ready for excretion.
Excretion: 98% of prednisolone is excreted in the urine as inactive conjugated metabolites.
Conjugated metabolites enter the kidney through the bloodstream and are filtered at the glomerulus into the urine.
The polar nature of the conjugated metabolites prevents them from being reabsorbed into the bloodstream through renal tubules.
2% may also be eliminated through biliary excretion into faeces .
Efficient liver metabolism and kidney function are essential for proper elimination to prevent drug accumulation and toxicity
MOA (D-outcome)
The desired short-term effects of prednisolone are anti-inflammatory in COPD exacerbation as it and helps alleviate airway oedema, improve bronchodilation, reduce mucus production, and control symptoms such as breathlessness and wheezing.
Normal response:
Inflammation is triggered by damage to mast cells which release histamine which cause vasodilation of blood vessels and increased permeability of capillaries, this increased blood flow causes an accumulation of phagocytes and lymphocytes.
During exacerbations, there are increased levels of eosinophils, neutrophils, lymphocytes, interleukins-6 and TNF-a levels which amplify the inflammatory response in the lungs. Checking eosinophils levels is a good predictor of inflammation levels for COPD with higher levels indicating increasing inflammation.
Prednisolone is a glucocorticoid receptor agonist binds to and activates intracellular glucocorticoid response elements , triggering changes in gene expression that result in various downstream effects over a period of hours to days; inhibits neutrophil apoptosis and demargination; inhibits phospholipase A2, to decrease arachidonic acid derivatives; suppresses NF-Kappa B, reducing cytokines (e.g., TNF-α, IL-1- IL-6) and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.
MOA Undesired effects
Prednisolone is a glucocorticoid receptor agonist that binds to intracellular glucocorticoid receptors throughout the body due to systemic circulation, and triggers changes in gene expression that result in various effects;
In the liver, glucocorticoids act directly to upregulate enzymes involved in gluconeogenesis and promote hepatic insulin resistance, which together accelerate the development of hyperglycaemia.
Prednisolone increases glycogenesis, by activating genes that control the metabolism of carbohydrates in the liver to release more glucose causing hyperglycemia. It also reduces glucose being absorbed from the blood by the muscle and fat cells, and it reduces the body’s sensitivity to insulin. For many people their blood sugar levels will return to normal once the prednisolone course is finished, however some patient can develop type two diabetes (T2DM) if they have been on lots of courses of steroids or are at increased risk of developing T2DM. A HBA1C blood test can check for diabetes.
Prednisolone suppresses the immune system, increasing infection risk. It raises neutrophil levels but limits their migration to infection sites, and it suppresses T and B-cell activity and suppresses cytokines.
Prednisolone increases the risk of osteoporosis by directly activating osteoclasts and deactivating osteoblasts, which leads to bone thinning and increased risk of fractures. It can also affect calcium absorption and excreation. COPD patient who take multiple courses of pred more than twice a year can be started on bone protection medication to reduce the risk of fracture, falls risk needs to be considered.
For one significant drug/drug interaction explain the mechanism of the interaction
Discuss management of the interaction
Prednisolone (pred) interaction with clarithromycin (clarith) is pharmacokinetic interaction as it affects the metabolism of prednisolone. This interaction is significant because it increases the plasma concentration of prednisolone, which could amplify side effects such as fluid retention, hyperglycemia, and mood changes. During a COPD exacerbation Clarithromycin is the drug of choice for patient who are penicillin allergic and do not respond to Doxycycline as per NICE guidelines. The relevance lies in the need to adjust the dose and closely monitor the patient for potential adverse effects while managing both the COPD exacerbation and ensuring the benefits of both medications are maximised safely.
BNF says it is a Severe (theoretical) interaction. Advises to avoid or monitor for adverse effects.
Clarithromycin is a potent inhibitor of liver enzyme CYP450 family and specifically CYP3A4, it decreases its production and activity by 75%. Clarithromycin binds to CYP3A4 and inhibits prednisolone from binding to the enzyme to be metabolised. This result will reduce prednisolone from being metabolised leading to increased drug plasma concentration to 113% causing increased side effects.
Management: I would consider lowering the dose of prednisolone to 20mg to be taken early in the morning as close to waking (to replicate body’s own natural cortisol peak) with food to slow the absorption.
Lowering the clarithromycin dose to 250 mg does not alter its inhibitory effects, half-life, or absorption, so adjusting pred dose is a more effective strategy to reduce interaction risks.
I will advise the patient to monitor for side effects such as raised blood sugars, blood pressure, oedema, sleep/mood disturbances. I will consider a further dose reduction in case the patient presents with side effects and will discuss the case with a doctor to safety net the patient.
I will consider repeating blood such as HBA1C, bone profile, urea and electrolytes and liver function in a week’s time. I will request GP to consider prescribing bone protection to avoid osteoporosis and fractures in at risk patients.
Patient example: How the PK/PD properties affect the choice of formulation for 10 marks need 2 examples
if you have not discussed absorption and distribution in Q1 -
Soluable formulation:
Mrs. L, a 68-year-old presents with IE COPD and is non-compliant with oral tablets. she is prescribed 30 mg OD of soluable prednisolone for 5 days.
(PK): Absorption and Onset of Action:
Soluble prednisolone dissolves in water, making it easier to swallow and is potentially absorbed faster in the small intestine compared to tablets that need to disintegrate. This ensures quick systemic availability, with a peak plasma concentration within 1-2 hours and 80% bioavailability to manage acute inflammation in COPD.
(PD): Anti-inflammatory Effect:
Soluable prednisolone is passively diffused into the blood stream and binds to plasma proteins albumin and transcortin to distribute prednisolone around the bodys to exert its glucocorticoid effects, such as reducing airway inflammation, improving airflow, and stablising the exacerbation.
Mr .M, a 80-year-old presents with IE COPD and experiences gastrointestinal (GI) discomfort, such as diarrhoea, when taking standard oral prednisolone. To manage their exacerbation and minimise GI side effects, they are prescribed an enteric-coated prednisolone formulation at 30mg for 5 days.
(PK): Delayed Release and Absorption
The enteric-coated formulation bypasses the stomach, dissolving in the alkaline environment of the small intestine. This reduces direct gastric irritation caused by steroids.
While the onset of action may be delayed compared to standard prednisolone tablets, the therapeutic effect remains unchanged, as the drug is absorbed in the intestine.
Prednisolone can irritate the stomach lining by reducing protective prostagalndins which help maintain the gastric mucosal barrier.
PD: anti-inflammatory effects: The delayed release does not impair the drug’s ability to exert its glucocorticoid effects (e.g., reducing inflammation in COPD exacerbation).
PD patient-specific factors:
Older patients such as Mr M are at higher risk of steroid-induced GI irritation due to age-related declines in mucosal protection. The enteric-coated formulation mitigates this risk, ensuring the patient can tolerate the medication.
Patient example How the PK/PD properties affect the choice of dose and frequency
Metabolism and elimination: 2 examples
Mr. A, a 65-year-old patient with liver cirrhosis and COPD exacerbation requires a short course of prednisolone.
(PK):
Hepatic impairment slows prednisolone metabolism, prolonging its half-life and increasing systemic drug levels.
Metabolic Pathway: Prednisolone is primarily metabolized in the liver by enzymes, including CYP3A4, through oxidation and reduction processes. It is also conjugated with glucuronic acid, and sulphate in phase 2 metabolism, making it more water-soluble for excretion.
Cirrhosis reduces the activity of liver enzymes CYP3A4 . This slows the conversion of prednisolone into its inactive metabolites. This can lead to drug accumulation and side effects like hyperglycemia, muscle weakness, and immunosuppression.
(PD):
Anti-inflammatory effects are critical for resolving the COPD exacerbation, so maintaining an effective dose is essential.
Start with a lower dose (e.g., 20 mg daily instead of 30 mg) to account for reduced metabolism.
Use a short course (e.g., 5 days) with close monitoring for side effects.
Monitor for signs of steroid toxicity (e.g., blood glucose, mental status changes).
A 80-year-old patient with very severe COPD is on a long-term palliative dose of prednisolone (10 mg daily) for chronic severe breathlessness. He experienced an exacerbation and was prescribed an increased dose of prednisolone 30 mg daily for 5 days, the dose needs to be slowly tapered down dose to his original 10mg OD. For example reducing by 5mg every 5 days, until he is back to his original 10mg OD dose.
The increased dose is needed to increase the anti-inflammatory effects of prednisolone and to ensure increased drug plasma concentrations.
Long-term steroid use is fraught with many side effects and it suppresses the hypothalamic-pituitary-adrenal (HPA) axis. Gradual tapering allows the HPA axis to recover gradually. abruptly stopping prednisolone in this example could lead to adrenal crisis and worsening symptoms of breathlessness. .
